Abstract Physicians recommend dietary interventions for management of cardiovascular disease, diabetes and many autoimmune diseases; however, there is a large gap in knowledge on the role of diet as a risk factor or potential therapy for chronic pain. Management of pain remains a substantial medical problem, in part, because of an incomplete understanding of the physiologic mechanisms for transduction and processing of noxious stimuli. Moreover, current analgesics are often limited by incomplete efficacy, unacceptable side effects or risk of dependency. New discoveries for both the treatment and prevention of chronic pain are essential, and investigating the relationship between diet and pain allows for the potential development of new therapies along with a better understanding of the mechanisms of persistent pain. Multiple studies have demonstrated that oxidized metabolites of linoleic acid (LA) or arachidonic acid (AA) have potent biological actions in activating transient receptor potential (TRP) channels, including TRPV1 and TRPA1, that are expressed on nociceptive neurons. Since LA and AA are essential omega-6 polyunsaturated fatty acids (PUFA), their physiologic levels are a function of dietary intake. Preliminary data presented in this application demonstrate that mice fed a 15-week high omega-6 diet exhibit changes in basal thermal and mechanical nociceptive thresholds and increased responses to noxious stimuli. However, there is still a large gap in knowledge as the mechanisms by which dietary omega-6 lipid intake modulate pain is not understood. Based on recent studies and our preliminary data, we propose to test the central hypothesis that increased dietary omega-6 PUFA leads to increased thermal hyperalgesia and mechanical allodynia via increased TRPV1 and TRPA1 activities. Diet-induced increased TRPV1 and TRPA1 activity could be a common mechanism among multiple chronic pain conditions and play a role in the transition from acute to chronic pain. The following aims will test the hypothesis: Specific Aim #1: Assess cellular lipid composition change following a 15-week high omega-6 diet and determine the role of the lipids in thermal and mechanical nociception. Specific Aims #2: Investigate the role of TRPV1 and TRPA1 in increased thermal and mechanical nociception following a high omega-6 diet. Specific Aim #3: Determine whether high lipid diet alters nociception in a sex-specific manner. This study is innovative in its rationale and potential for identifying an environmental factor that could predispose and possibly predict pain response. This project may also lead to novel therapeutic approaches for treatment and prevention of chronic pain conditions. Moreover, the techniques and research methods provide an ideal training vehicle for my career as an academic physician-scientist.